Translational modelling to predict human pharmacokinetics and pharmacodynamics of a Bruton's tyrosine kinase-targeted protein degrader BGB-16673

Background and purpose: Bifunctional small molecule degraders, which link the target protein with E3 ubiquitin Ligase, could lead to the efficient degradation of the target protein. BGB-16673 is a Bruton's tyrosine kinase (Btk) degrader. A translational PK/PD modelling approach was used to predict the human Btk degradation of BGB-16673 from preclinical in vitro and in vivo data.

Experimental approach: A simplified mechanistic PK/PD model was used to establish the correlation between the in vitro and in vivo Btk degradation by BGB-16673 in a mouse model. Human and mouse species differences were compared using the parameters generated from in vitro human or mouse blood, and human or mouse serum spiked TMD-8 cells. Human PD was then predicted using the simplified mechanistic PK/PD model.

Key results: BGB-16673 showed potent Btk degradation in mouse whole blood, human whole blood, and TMD-8 tumour cells in vitro. Furthermore, BGB-16673 showed Btk degradation in a murine TMD-8 xenograft model in vivo. The PK/PD model predicted human PD and the observed Btk degradation in clinical studies both showed robust Btk degradation in blood and tumour at clinical dose range.

Conclusion and implications: The presented simplified mechanistic model with reduced number of model parameters is practically easier to be applied to research projects compared with the full mechanistic model. It can be used as a tool to better understand the PK/PD behaviour for targeted protein degraders and increase the confidence when moving to the clinical stage.

BTK; cancer pharmacology; clinical translation; mathematical model; pharmacokinetics‐pharmacodynamics; targeted protein degrader.